T-cell lymphomas represent a heterogeneous and understudied group of malignancies of the immune system with poor response to standard therapy in most cases. However, subsets of patients have excellent outcomes for unknown reasons. The goal of this project is to develop personalized medicine strategies for patients with anaplastic large cell lymphoma (ALCL), one of the most common types of T-cell lymphoma. Specifically, we will use genomic discovery to develop genetic tests that: (1) identify specific drug targets in tumor tissue and guide targeted therapy, and (2) distinguish highly aggressive tumors from less aggressive so that the intensity of therapy can be individualized. Currently, only one gene, ALK, is tested to classify ALCLs. Our team has identified chromosome abnormalities of two other genes in ALCL, DUSP22 and TP63. Five-year survival rates for ALCL patients with abnormal DUSP22 are 90%, compared to only 17% for patients with abnormal TP63. The reasons for this marked difference in survival remain unknown, and both groups of patients currently receive the same treatment. Furthermore, some ALCLs grow in response to a group of growth-promoting proteins collectively known as JAK-STAT3. Importantly, tumor growth caused by JAK-STAT3 can be blocked by drugs that target these proteins. However, the relationship between JAK-STAT3 proteins and DUSP22 and TP63 abnormalities has not been studied. In Aim 1, we will determine the relationship of DUSP22- and TP63- rearranged ALCLs to dysregulation of the JAK-STAT3 pathway using a combination of RNA sequencing to examine gene expression and mass spectrometry to assess protein activation. We anticipate developing laboratory tests that differentiate these distinct types of ALCL, and also identifying key growth-promoting proteins that could lead to new targeted therapies for ALCLs that lack JAK-STAT. In Aim 2, we will identify the spectrum and role of mutations in ALCL. Specifically, we have discovered mutations that alter proteins called basic helix-loop-helix (bHLH) transcription factors that are key regulators of gene expression in lymphocytes. We anticipate that bHLH gene mutations will cooperate with other abnormalities (e.g., DUSP22) to promote tumor growth, and that understanding this cooperation will lead to new therapies for ALCLs. In Aim 3, we will characterize the methylome of DUSP22-rearranged and other ALCLs to identify key differences in DNA methylation, a major factor controlling the specific genes that are expressed in a given cell. Our data suggest that ALCLs vary widely in their degree of DNA methylation. We anticipate finding that the methylation pattern in ALCLs with DUSP22 abnormalities leads to expression of proteins known as cancer-testis antigens, suggesting that these tumors may be particularly sensitive to therapies that enhance antitumor responses of the host immune system. In contrast, we anticipate that ALCLs with excessive methylation will respond to drugs designed to reduce DNA methylation. All 3 Project Aims will utilize the Pathology and Bioinformatics Cores. Aim 2 will utilize the Functional Genomics and Preclinical Models and Therapeutics Cores.